• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    NEW MATERIAL:The compound of formulaI(R is t-butanecarbonyl, cyclopropanecarbonyl, cyclohexanecarbonyl or adamantanecarbonyl bonded to the alpha- amino group of the amino acid; A is residue of glycine, sarcosine or alpha-D-amino acid, and the alpha-carbonyl and S together form a thiol ester bond) and its salt. EXAMPLE:N-[3-(N-Cyclohexanecarbonyl-D-alanylthio)-2-D-methylpropanoyl]-L- proline. USE:Remedy for hypertension and cardiac insufficiency. It has mild hypotensive activity at the initial stage of administration, and little possibility of developing orthostatic hypotension. PROCESS:The compound of formulaIcan be prepared, e.g. by reacting the compound of formula R-A'-OH (A' is residue of glycine, sarcosine or alpha-D-amino acid) or its reactive derivative with the compound of formula II (R' is H or carboxyl-protecting group).
    公开号:SU1272982A3
    申请号:SU823514502
    申请日:1982-11-25
    公开日:1986-11-23
    发明作者:Танака Садао；Куромару Киенори；Фудзимура Ясуо；Мацунага Исао；Иваока Томояси；Обатаке Норико；Аоно Дзунитиро；Хинохара Есиказу；Накано Хидеки；Фукусима Масафуми；Набата Хироюки；Сакаи Казусиге；Хата Сун-Ити
    申请人:Чугаи Сейяку Кабусики Кайся (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to the preparation of novel strait derivatives of the general formula (RrA-S-CH CHCO-K COOIi) where R is an acyl group, an amino acid linked to the oL-amino group and is selected from the group consisting of cyclopropanecarbonyl, cyclehexanecarbonyl, or adamantanecarbonyl groups; A is a glycine, sarcoein or ot-D-amino acid residue and has a cA-carbonyl group which forms a thiol ester bond to a sulfur atom; or their pharmaceutically acceptable salts of salts with hypotensive action. The aim of the invention is to develop, on the basis of an excellent method, a method of producing new compounds with valuable pharmacological properties. Example I. Obtaining K-substituted amino acids. a) D-Handan 4.5 g is dissolved in 230 PP of aqueous 1N sodium carbonate solution with stirring. To this solution, 100 ml of tetrahydrofuran containing 9.0 g of cyclohexanecarbonyl chloride are added dropwise at 5, the mixture is stirred at this temperature for 30 minutes, then stirred at room temperature for 5 hours. Thereafter, the reaction mixture is added 2N., HC1 solution to adjust the pH of the mixture between I and 2. The reaction mixture is extracted with ethyl acetate, the organic layer is washed with a saturated solution of NaCl and dried over magnesium sulfate. The filtrate is evaporated in vacuo to give the crude product. Upon recrystallization1 {and it from ethyl acetate / n-hexane, 4.65 g of K-cyclohexanecarbonyl-O-alanine are obtained. + 26.6 °. b) The ester of adamantanecarboxylic acid and H-oxysuc1 dinamide (3.0 g) is dissolved in 30 ml of hydrogravide of furan. To this solution add 5 ml of water containing 0.89 g of Dlanin and 1.1 g of triethylamine, and the mixture is stirred overnight at 5 ° C. After removing the tetrahydrouran, water is added to the residue and then 2n. a solution of HC for it to bring the pH of the mixture between 1 and 2. Then the mixture is treated in the same way as in example 1a, 0.38 g of H-adamantanecarbonyl-Vlanin is obtained. a3j, + P, 6 (C 1.0, MeOH). The compounds listed below are prepared by one of the methods described in Example 1a and 6. N-Substituted Amino Acids: Adam Method: ntancarbonylglycine N Cyclohexanecarbonyl-ifhenylalanine. A N-Cyclohexanecarbonyl-Omethionna N-Cyclohexanecarbonyl-Vlutamine Y-Cyclopropanecarbonyl-Valanina N-Cyclohexanecarbonylglycine K-cyclohexanecarbonyl-. sarcosy On N-Cyclopropanecarbonylglycine Example 2. S- (3- (H-Cyclohexanecarbonyl-B-alan), -2-B-methylpropanocl-L-Proline. Dissolved in 80 ml of dry tetrahydrofuran, 5.98 g K-cyclohexanecar, bonil- B-alanine. To the solution was added 5.84 g of carbonyldinimidazole at -18 ° C while stirring and cooling the mixture with ice. At this temperature the mixture was stirred for 1 hour and then 6.29 g of N- (3 mercapto-2-B -methylpropanoyl) -l-prolca, followed by stirring at -leC for 30 minutes, then at room temperature for 1 hour. After completion of the reaction and the mixture is evaporated in vacuo, removing the solvent. 50 ml of water is added to the residue and 2N hydrochloric acid is added to the mixture to adjust the pH between 1 and 2. The mixture is extracted with ethyl acetate and the ethyl acetate layer is washed with an NaCl solution and dried over sulfate magnesium and evaporated in vacuo. 120 ml of acetonitrile is added to the residue and then 6 np of dicyclohexylamine (DCA) is added. The mixture is stirred for 1 hour at room temperature. After standing overnight, the precipitate was filtered and dried in air, obtaining a crude DCA salt (12.35 g). The crude salt was suspended in 300 ml of acetonitrile, and the suspension was heated under reflux for 30 minutes. After cooling, the precipitate is collected by settling and air dried, yielding 12.20 g of the white salt of DCA. The DCA salt (12.2 g) is suspended in 90 ml of ethyl acetate, 60 ml of a 0.5N aqueous solution of potassium bisulfate are added to the suspension, and the mixture is shaken. The organic layer is washed with distilled water, dried over magnesium sulphate and evaporated in vacuo to give a rubber-like substance (8.64 g). By NMR and thin layer chromatography, it was established that this substance is identical to the proposed compound. Example 3. N-GZ- (N-Cyclohexanecarbonylglycylthio) -2-0-methylpropanoyl-L-proline. 1.02 g of N-cyclohexanecarbonylglycine is dissolved in 10 MP of dry tetrahydrofuran. To the solution was added 20 ml of dry tetrahydrofuran containing 1.07 g of carbonyldiimidazole while stirring with ice-cooling. The mixture is stirred at this temperature for I h and then 6 ml of dry tetra hydrofuran containing 1.09 g of N- (3 mercapto-2-b-methylpropanoyl) -b-proline are added, followed by stirring at | -20 ° C for 30 minutes, then at {room temperature for 1 hour. After completion of the reaction, the mixture is evaporated in vacuo to remove the solvent. The residue is subjected to chromatographic purification on a column of silica gel (2x35 cm), using as eluent a mixture of methanol and chloroform (from 1: 100 to 3: 100). The fractions containing the final product are combined and evaporated in vacuo to give a rubbery substance (1.16 g). By NMR analysis and thin layer chromatography, it was established that this substance is identical to the proposed compound. PRI me R A. (N-Cyclopropanopancabronyl-D-apantio) -2-D-methylpropanoyl-L-pollin. In 14 ml of dry tetrahydrofuran, 635 mg of N-cyclopropanecarbonyl-P-alanine and 0.70 ml of triethylamine are dissolved. To this solution was added 0.48 ml of ethyl chloroformate while stirring and cooling the mixture with ice. The mixture is stirred at this temperature for I5 minutes and thereafter, 09 g of N- (3mercapto-2-B-methylpropanoyl) -L-proline and 10 MP of dry tetrahydrofuran containing 0.70 mp of trietclamine are added, followed by stirring at for 15 min, then at 5 ° C overnight. After completion of the reaction, the mixture is evaporated in vacuo at 30-35 seconds to remove the solvent. 10 ml of water was added to the residue, and 2N hydrochloric acid was added to the mixture to adjust the pH between 1 and 2. The mixture was extracted with chloroform, and the chloroform layer was washed with saturated NaCl solution, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography on a column of silica gel (2 x X 35 cm), using a mixture of methanol and chloroform (1: 100 to 3: 100) as eluent. The fractions containing the final product are combined and evaporated in vacuo to give 395 mg of rubber-like substance. By NMR analysis and thin-layer chromatography, it was established that this substance is identical to the intended compound. EXAMPLE 5 (N-tKnoreK-Carbonyl-M-methylglycylthio) -2-D ethylpropanoylZ-L-proline. The procedure of Example 4 is repeated with the exception that N-cyclohexanarbonylglycine is replaced by N-cyclo-xane-carbonyl-N-methylglycine (1.09 g), arbonyldiimidazop (1.09 g) and N- (3ercapto-2-0-metstrspanoyl) - B-proin (1.09 g). 0.76 g of rubber-like substance is obtained. By NMR analysis and thin layer chromatography, it was established that this substance is identical to the proposed compound. PRI me R 6. (N-Cyclopropancanoylglycylthio) -2-D-methylpropanoyl-b-Proline. The procedure of Example 4 is repeated with the exception that N-cyclohexanecarbonylglycine is replaced by N-cyclopropanecarbonylglycine (0.96 g), carbonyldiimidazole (1.09 g) and H- (3-mercapto-2-B-methylpropanoyl) -b -proline (1.09 g). Obtain 0.4 g of rubber-like substance. Using the methods of the JMAE-analysis and thin-layer chromatography, it was established that these substances are identical to the proposed compound. Example. (N-Adamantanecarbonylglycylthio) -2-0-methylpropanoyl -b-proline. The procedure of Example 4 is repeated with the exception that N-cyclohexanecarbonylglycine is replaced with H H adaman tancarbonyl glycine (1.42 g), carbonyldiimidazole (1.09 g) and H (3-mercapto-2-0-methylpropanone) -1.- proline (1.09 g). 1.7 g of reusable substance is obtained. The method of NMR analysis and thin layer chromatography established that this substance is identical to the proposed connection. Example N-t3 (N-Cyclohexancabronyl-D-fennalaniltid) -2 D methyl propanoyl} -l-proline. The procedure of Example 4 is repeated with the exception that H-cyclohexanecarbonylglycine is replaced by N-cyclohexanecarbonyl-B-phenylalanine (1.54 g carbonyldiimidazrl (1.09 i) and N-3 mercapto-2-B-methylpropanyl) -b-proline (1.09 g). Obtain 0.97 g of rubber-like substance. Using NMR analysis and thin layer chromatography, it was established that this substance is identical to the proposed compound. PRI me R 9. (N-cyclohexancabonyl-D-leucylthio) -2-D methylpropropanyl-L-proline. The procedure of Example 4 is repeated, with the exception that N-cyclohexancar nylglycine is replaced by N-cyclohexane carbonyl-Gh-leucine (, 2Q g), carbonyldiimidazole (0.97 g) and M- (3-measure-2- B-methylpropanoyl) -l-proline (0.98 g). 1.17 g of a rubbery substance are obtained. NMR-ana methods
    LIZA and thin-layer chromatography established that this substance is identical to the proposed connection.
    and thin-layer chromatography found that this substance is similar to the proposed connection. Example 10 "(N-Cyclohexancabonyl-D-triptophiltio) -2-D-methylpropanoyl-L-proline. The procedure of Example 4 is repeated with the exception that N-cyclohexanecarbonylglycine is replaced by N-cyclohexanecarbonyl-B-tryptophan (1.75 g), carbonylDicmidazole (1.09 g) and N- (3mercapto-2-P-methylpropanoyl) - L-proline (1.09 g). Obtain 0.8 g of rubber-like substance. By NMR analysis and thin layer chromatography, it was established that this substance is similar to the proposed compound. PRI me R 11. (N-Cyclohexancabronyl-D-phenylglycylthio) -2-D-methylpropanoyl l-L-proline. The procedure of Example 4 is repeated, with the exception that N-cyclohexanecarbonylglycine is replaced by L-diclohexanecarbonyl-P-phenylglycine (1.30 g), carbonyldiimidazole (0.97 g) and N- (3-mercato-2-B-methylpropanoyl) - L-nplin (0.98 g). 0.35 g of rubber-like substance is obtained. By NMR analysis and thin layer chromatography, it was established that this substance is similar to the proposed compound. Example 12. (N-Cyclohexanecarbonyl-B-methionylthio) -2-B-methylpropanoylj-L-lrolin. The procedure of Example 4 is repeated with the exception that the Cycliclohexanecarbonylglycine is replaced by Ncyclohexanecarbonylmethionine (1.30 g), carbonyldiimidazole (1.09 g) and N- (3-mercapto-2-B-metsh1propanosh1) L-proline (1 , 09 g). Obtain 0.59 g of rubber-like substance. By NMR analysis and thin layer chromatography, it was established that this substance is similar to the proposed compound. Example 13. (N-Cyclohexanecarboni. P-B-glutaminylthio) -2-B-methylpropanoyl -b-proline. The procedure of Example 4 is repeated with the exception that N-cyclohexanecarbonylglycine is replaced by H, cyclohexanecarbonylglutamine (0.5 i;), carbonyldiimidazole (0.4 g) and K- (3-mercapto-2-B-methylpropanosh1) -L- proline (0.41 g). 0.3 g of rubber-like substance is obtained by NMR analysis. EXAMPLE 1. (H-adaman- .tankaroish1 0-alanylthio) -2-B-methylpropanoyl -1, -proline. Repeat the procedure of Example 4 with the exception that L7 cyclohexanecarbonylglycine is replaced by N-adaman tancarbonyl-P-alanine (1.2 g), carbonyldiimidazole (0.97 g) and H- (3-mercapto-2-B-methylpropanoyl) -b-proline (0, 98 g). Obtain 1.02 g of rubber-like substance. By NMR analysis and thin layer chromatography, it was established that this substance is similar to the proposed compound. Example 15 (an example using K, K-thionylimidazole). Thionyl chloride (5.79 g) was added to dry dichloromethane (80 ml) and cooled to -15 ° C with stirring. N-trimetidsilyl imidazole (15 g) was added to the solution, and the solution was stirred at -13 ° C for 1 hour, and then N-cyclohexanecarbonyl D-aLanine (8.8 g) was added and stirring was performed with the same temperature for 30 minutes. After adding to the mix. sy 3-mercapto-2-B-matyl propanoyl-b-proline (9.5 g) and stirring it for i h the pH of the mixture is adjusted to 1 with 3 n sHH, the organic layer is separated and washed twice with saturated aqueous NaCl solution Dry over magnesium sulfate and evaporate under reduced pressure to remove dichloromethane. The residue was subjected to silica gel column chromatography (2.5 x 50 cm column), and the fractions containing the desired compound were collected, combined, and evaporated under reduced pressure to give 12.5 g (cyclohexanecarbonyl-p-alanylthio) -2-B- methylpropanoyl β-proline as a colorless solid, such as burnt sugar. Example 16 (an example using pivaloyl chloride as a mixed acid anhydride). To a solution of N-cyclopropanecarbonyl-D-alanine (635 mg) and triethylamine (0.70 ml) in dry dioxane (14 ml) was added pivaloyl chloride (0.35 ml), and the solution was cooled to -15 ° C with stirring. Stirring is continued for 15 minutes; a solution of H- (3-mercapto-2-B-methyl propanoyl) -b-proline (1.09 g) and triethylamine (0.70 ml) in dry dioxane (10 ml) was added to the mixture and stirred at -15 ° C for 20 min, and then at 5 ° C overnight. The racratic mixture is evaporated under reduced pressure, and water is added to the residue. After the pH was adjusted to 4 with 3NHC I, extraction was performed with chloroform. The chloroform layer is washed twice with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure to remove the solvent. The residue was subjected to silica gel column chromatography using a 2.5 x 50 cm column, and the fractions containing product were collected and evaporated under reduced pressure, to give 320 mg (cyclopropanacarbonyl-D-gelanyltio) -2-B-methylpropanoyl j L-proline in form of gummy substance. Example 17. From (K-cyclohexanecarbonyl-P-alanylthio) 2-B-methylpropanoylJ-L-proline, various salts are formed: a) Calcium salt. A sample (3.98 g) of the compound prepared in Example 3 is dissolved in 40 cl of methanol. 0.84 g of calcium acetate hydrate is added to this solution, the mixture is heated under reflux for an hour. The insoluble matter is filtered off and the filtrate is evaporated. in a vacuum. Chloroform is added to the residue, the mixture is filtered and the mixture is evaporated in vacuo. Diethyl ether was added to the residue and the mixture was filtered and air-dried to obtain the calcium salt of Example 3 (3.40 g) Gal -47.2 ° (C 1.0, MeOH). b) Magnesium salt. Procedure a was repeated using 09 g of the compound prepared in Example 3 or 5 and 0.722 g of magnesium acetate tetrahydrate. 42 g of a magnesium salt of the compound are obtained from -46.6 ° (C "1.0, MeOH) reamer 31a5c), Lysine salt. , 1.19 g of the compound prepared in Example 3 is dissolved in 22 MP of methanol. 416 g of lysine is added to this solution, the mixture is stirred at room temperature for 1 h and evaporated in vacuo. Chloroform is added to the residue, the mixture is filtered and evaporated in vacuo. Dimethyl ether was added to the residue, and the product was filtered with suction to give the lysine salt of the compound of Example 3 (1 ,, 54 g). -.23, G (C 1.0, MeOH). d) Sodium salt. Dissolve in 25 ml of methanol, a sample (2.27 g) of the compound prepared in Example 3. To this solution add 0.514 g of sodium acetate, the mixture is stirred at room temperature for 30 minutes and evaporated in vacuo. 200 ml of a mixture of methanol and chloroform (3: 100 by volume) are added to the residue, the resulting mixture is filtered and evaporated in vacuo. The residue is dissolved in methanol, the solution is filtered and evaporated in a vacuum. Ethyl acetate is added to the residue, and the product is filtered off with suction to obtain the sodium salt of the compound of Example 3 (1.85 g). A | -26.7 (, 0 MeOH). e) Dicyclohexylamine salt. A 13.1 g sample of the compound from Example 3 is dissolved in 120 ml of acetonitrile. To this solution, 6 ml of dicyclohexylamine are added while stirring. The mixture is further stirred for 30 minutes, then left overnight. The residue is filtered with suction and dried in air. The resulting crude crystals are suspended in 300 ml of acetonitrile, and the suspension is refluxed for 30 minutes. The suspension is cooled, the crystals are filtered off with suction and dried in air to give the dicyclohexylamine salt of the compound of Example 3 (12.2 g). 1aH - 24.5 (C "1.0, MeOH). The resulting proline derivatives and their pharmaceutically acceptable salts prevent the formation of angiotensin II from angiotensin I by inhibiting the activity of the enzyme that converts angiotensin. Therefore, they are useful for reducing the elevated pressure caused by angiotensin II and as agents for treating heart failure. The activity of some of the compounds obtained in relation to the inhibition of the enzyme that converts angiotensin was measured. 1. Method. An angiotensin converting enzyme was extracted from rabbit lung. 0.6 ml of a buffer solution (pH 8.3), 0.1 ml of boric acid — sodium carbonate, 0.02 ml of O, a 111-molar solution of boric acid buffer — sodium carbonate (pH 8.3) containing 25 mmol / l benzoylglycyl histidyl leucine substrate and 0.1 ml of a 111-molar solution of boric acid-sodium carbonate buffer (pH 8.3) containing from 10 to 10 mol / l of test compounds (13 final products are listed in Table 1 ) and pre-cultured at 37 ° C for 5-10 min. Then 0.1 ml of an enzyme solution (powder in acetone) is added to each tube, and each mixture is cultured for 30 minutes at. Benzoyl glycine, prepared with an enzyme, is extracted with ethyl acetate in the presence of hydrochloric acid, and its amount is determined by UV conversion at 228%. The enzyme activity in the presence of test compounds relative to activity in the absence of test compounds taken as 00 is determined. The concentration of each test compound at which the relative activity of the enzyme is 50% is called the activity of each test compound in inhibiting the activity of the enzyme and is denoted by Ij. 2 Results yes, iy in table.1. T a b l i c i 1,6x10 4,8x10 1,3x50 4,0x10 1,8x10 2,4x10 1,0x10 1,5x10 1,7x10 Note. Compound 1: N- 3- (H-cyclohexanecarbonyl-Vapanylthio) -2-0-methypropanoyl-L-pro ling; 2: N- (3- (N-cyclopropanaparbonyl1) -alynylthio) -2-B-methylpropanoyl1-L proline; 3: (M-cyclohexanecarbonylglycylthio) -2-P-methylpropanoyl-L-proline; four; (N-cyclohexanecarbonyl-N-methylglycylthio) -2-P-methylpropanoyl1-1.-proline; 5: (H-cyclo-propanecarbonylglycylthy .o) -2-B-methylpropanoyl-L-proline; 6: N-t3- (N-aflaMaH tancarbonylglycylthio) -2-Yu-methylpropanoyl-b-prol n; 7: K- {3- (K-cyclohexancar6onyl-B-fensh1-alanylthio) -20-methylpropanoyl-L-proline; 8: N-13 (I-cyclohexanecarbonyl-B-neucylthio) 2-0-methylpropanoyl-L-prolii; 9: (N-cyclohexanecarbonyl-B-tryptophyptio) -f 2-p-methylpropanoyl 1-L-proline 10; (N-cyclohexancar bonyl-B-phenylglycylthio) -2-B-methylpropioyl-L-proline} 11: (K-cyclohexanecarbo-nip-B-methionylthio) -2-B-methylpropanosh13-b-proline 5 12; H-13- (H-Cyclohex. Sancarbonyl-B-glutaminylthio) -2-D-Methylpropanosh1-L-proline} 13: (Na admantanecarbonyl-B-adanylthio) -2-Vmethylpropanoyl-L-proline. For the comparative analysis, the following compounds were proposed: - A) N-3- (N-imiojoreK -sancarbonyu1-B-alanylthio) -2-B-methylpropanoyl-1-L-proline; known - B) N-СЗ- (L-acetyl-L-prolylthio) -2-B-methyl propanoyl-L-proline; C) (N-aue-Sh1-b-phenyl-alaniptio) -propanoyl 1-b-proline; B) L-C3- (H-tert.butyloxycarbonylglycylthio) -2-B-methylpropanoyl L-proline; E) (N-benzoyl-L-phenyl-alanylthio) -2-B-metnpropanoyl} -l-proline; F) M-Hz- (K-cyclopentanecarbonyl1.-Elanilt 1o) -2-B-methylpropanosh1 l-Lprolin, Test method. I) Vitro enzymatic hydrolysis. 1 MP of a 5% rat hepatic homogenate in 0.1 M kgzliphosphate buffer (pH 7) was mixed with 1 m 10 M solution of the test compound in the same phosphate buffer, after which the mixture was incubated at 37 ° C for a given period time specified in the table.2. To the 100 µl of this mixture, 6 drops of hydrochloric acid 1 and hydrochloric acid and 5 ml of ethyl acetate were added. After megachic stirring for 10 minutes, the mixture was centrifuged, and the resulting ethyl acetate layer was separated and evaporated. The residue was dissolved in ml of water and 6.5 μl of 0.4 M phosphate buffer (pH 6.85) and 5 μl of 5 10 M (H-p- (2-benzimidazolyl) -phenylmaleimide (BIFM) were added to the aqueous solution, and then the mixture was left to stand for AO minutes at 0 ° C. The reduction was calculated by exciting the sample at 310 nm and measuring the radiation; not at 365 nm (measurement limit: more than 0.1 µg 3-mercapto-2-B- methylpropanol-L-proline). 2) Inhibition of angiotensin-1 vasoconstrictor reaction. The test compound was administered through the mouth in dosages of 0.4 µmol / kg body weight of the animal (rat) j After anesthesia, and after a prescribed period of time after injection into the body of the experimental animals, angiotensin 1 was injected intravenously at a dosage of 300 mg / kg, after which inhibition of the angiotensin-1 vasoconstrictive reaction was observed. Compounds A, B and, which were those As in the case of the implementation of the test procedure 1), the test results are given in s a.2. As illustrated by the results of the tests listed in Table 2, the known compounds exhibit a higher sensitivity of the thioliferous bond to enzymatically "in vitro) hydrolysis than the proposed compounds. The known compounds, with the exception of compound B, were subjected to enzymatic hydrolysis at a destruction level of more than 50% after incubation for 60 minutes with the formation of an appropriate amount of free mercapto groups. On the other hand, although compound B shows significant resistance to the enzyme 82 hydrate of the thiol-ester group, it is able to inhibit the vasoconstrictor response to angystezin I at a level of only about 50% of the level achieved using the intended compounds. table 2
     n is the number of test cycles.
    权利要求:
    Claims (2)
    [1]
    1. The method of producing proline of General formula
    CH, I 3
    R r AS-CH 2 CHC0-N
    С00Н where R ( is the acyl group associated with the (-amino group of the amino acid and selected from the group consisting of cyclopropanecarbonyl, cyclohexanecarbonyl or adamantanecarbonyl groups;
    A is the residue of glycine, sarcosine or d-D-amino acid and has a << carbonyl group, which forms a thiol ester bond with a sulfur atom;
    or their pharmaceutically acceptable salts, characterized in that the compound of General formula
    Y - A ’- OH, where A is the residue of glycine, sarcosine, or a protected or unprotected << D-amino acid;
    R, has the indicated meanings, as a mixed acid anhydride or N-acylimidazolyl derivative, is reacted with an N- (3-mercapto-2-B-methyl-propanoyl) L-proline of the formula
    SB hs-ch 2 chco-n (J sone in an inert organic solvent at a temperature of from -20 to + 20 ° C, followed by removal of the protective group and isolation of the target product in free form or in the form of a pharmaceutically acceptable salt.
    [2]
    2. Method ποπ.Ι, characterized in that; o tetrahydrofuran, dioxane or dichloromethane are used as an inert organic solvent.
    类似技术:
    公开号 | 公开日 | 专利标题
    US4513009A|1985-04-23|Aminoacid derivatives and their therapeutic applications
    EP0611375A1|1994-08-24|Peptides inhibiting il-1 beta release
    PT86366B|1990-11-20|METHOD FOR THE PREPARATION OF PHOSPHINIC ACID AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
    PT90659B|1994-10-31|PROCESS FOR THE PREPARATION OF RENIN INHIBITORS CONTAINING DIOIS
    EP0331921A1|1989-09-13|Renin inhibitors containing alpha-heteroatom amino acids
    CS213370B2|1982-04-09|Method of making the derivatives of dehydrogenated cyclic iminoacids
    EP0012845A1|1980-07-09|Tetrahydroisoquinoline compounds, process for preparing same and pharmaceutical compositions containing them
    PL126126B1|1983-07-30|Process for preparing novel derivatives of dipeptides
    HUT70936A|1995-11-28|Substituted dialkyl-thioethers, process for producing them and pharmaceutical compositions containing them
    US3821188A|1974-06-28|Proline and pyroglutamic acid containing tripeptides
    SU1272982A3|1986-11-23|Method of producing proline derivatives or pharmaceutically acceptable salts thereof
    US4346105A|1982-08-24|Novel substituted phenylacetic acid amide compounds
    US4250192A|1981-02-10|Novel substituted phenylacetic acid amide compounds
    US4420490A|1983-12-13|Substituted phenylacetic acid amide compounds
    US6403561B1|2002-06-11|Tripeptidylpeptidase inhibitors
    WO1999003878A2|1999-01-28|Inhibitors of metalloproteinases, their therapeutic use, and process for the production of the starting compound in their synthesis
    PL167915B1|1995-12-30|Method of obtaining n-| carbonyl dipeptide hypertensors
    US4678800A|1987-07-07|Gamma-r-glutamoyl derivatives
    US4665087A|1987-05-12|1-|-indoline derivatives
    FI64349C|1983-11-10|FRAMEWORK FOR THE FRAMEWORK OF ETAPER THERAPEUTIC ANALYZLE L-PYROGLUTAMYL-L-HISTIDYL-GLYCINE OCH DESS SALTER
    US4474799A|1984-10-02|Enkephalinase inhibitors
    SU1316556A3|1987-06-07|Method of producing proline derivatives or rharmaceuticall asseptable
    US4474795A|1984-10-02|Enkephalinase inhibitors
    RU2168493C2|2001-06-10|Derivatives of l-arginine, method of their synthesis, pharmaceutical composition inhibiting activity of no-synthase
    SU1241988A3|1986-06-30|Method of producing chlorine hydrate of | 1-/-/| amino-1-oxopropyl/-octahydro-1h-indol-2-carboxylic acid as,s,s,s-or s,s,r,s-isomers
    同族专利:
    公开号 | 公开日
    ATA238582A|1989-11-15|
    AT390619B|1990-06-11|
    ZA823779B|1984-01-25|
    BE893553A|1982-12-17|
    JPS57209270A|1982-12-22|
    JPS6313433B2|1988-03-25|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GR73585B|1978-09-11|1984-03-26|Univ Miami|
    ZA802420B|1979-05-18|1981-04-29|Squibb & Sons Inc|Aminoacyl derivatives of mercaptoacyl amino acids|
    PT70158A1|1980-03-03|1982-03-01|Univ Miami|Process for preparing anti-hypertensive agents|DE60336485D1|2002-08-19|2011-05-05|Pfizer|COMBINATION THERAPY AGAINST HYPERPROLIFERATIVE DISEASES|
    US7741317B2|2005-10-21|2010-06-22|Bristol-Myers Squibb Company|LXR modulators|
    US7888376B2|2005-11-23|2011-02-15|Bristol-Myers Squibb Company|Heterocyclic CETP inhibitors|
    WO2008070496A2|2006-12-01|2008-06-12|Bristol-Myers Squibb Company|N--2, 2--propan-1-amine derivatives as cetp inhibitors for the treatment of atherosclerosis and cardiovascular diseases|
    CA2909442A1|2013-04-17|2014-10-23|Pfizer Inc.|N-piperidin-3-ylbenzamide derivatives for treating cardiovascular diseases|
    WO2016055901A1|2014-10-08|2016-04-14|Pfizer Inc.|Substituted amide compounds|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP56094002A|JPS6313433B2|1981-06-19|1981-06-19|
    [返回顶部]